The long-term objective of this work is a comprehensive analysis of the cardioprotective effects of volatile anesthetics. These agents are capable of reducing reversible and irreversible myocardial injury following coronary artery occlusion and reperfusion. Recently, it was found that a prior, brief exposure to the volatile anesthetic, isoflurane, can reduce myocardial infarct size after its discontinuation. This phenomenon has a strong similarity to ischemic preconditioning (IPC) in which a brief period of coronary artery occlusion and reperfusion renders myocardium resistant to infarction after a subsequent prolonged ischemic insult. Anesthetic-induced preconditioning (APC) demonstrates a powerful cardioprotective effect with short and longterm memories. The major hypothesis to be tested in the present investigation is that volatile anesthetics directly produce APC against myocardial infarction. The intracellular signal transduction pathways for APC will be characterized in an in vivo rat model of myocardial infarction (measured by triphenyltetrazolium histochemical staining). Specific Aims include: Aim I: To characterize the efficacy of APC against myocardial infarction. Aim II: To identify signal transduction pathways (including role of adenosine receptors, protein kinase C, protein tyrosine kinase, mitogen-activated protein kinases, and reactive oxygen species) in APC. Aim III: To determine relative importance of sarcolemmal versus mitochondrial K(ATP) channels in APC. Aim IV: To delineate genetic factors involved in APC and/or IPC. Because of the large number of patients with coronary artery disease undergoing anesthesia for surgery and the morbidity and mortality associated with perioperative myocardial ischemia and infarction, the proposed research represents an investigation into a clinically relevant problem. Volatile anesthetics have recently been shown to produce APC in patients undergoing coronary artery bypass graft surgery. This proposal will systematically delineate mechanisms and subcellular loci responsible for the novel and unique cardioprotective effects of volatile anesthetics against ischemia and reperfusion injury.